The present invention relates to pharmaceutical preformulations in the form of a dry extract of natural mixtures of conjugated equine estrogens, in particular of mixtures of conjugated estrogens obtained from the urine of pregnant mares. Dry extracts as preformulations of these natural mixtures of conjugated estrogens suitable for the production of solid galenic forms, e.g. for tabletting, are thereby provided. The invention furthermore relates to a method for the production of these preformulations in the form of a dry extract.
Estrogens are used in medicine for hormone replacement therapy. In particular, estrogen mixtures are used for the treatment and prophylaxis of the disorders of the climacteric period which occur in women after natural or artificial menopause. In this case, natural mixtures of conjugated equine estrogens such as are found in the urine of pregnant mares have proved particularly effective and readily compatible.
The dissolved solids content in the urine of pregnant mares (=pregnant mares' urine, abbreviated hereafter as “PMU”) can naturally vary within wide ranges, and may generally lie in a range of 40 to 90 g dry matter per liter. In addition to urea and other usual urine contents, phenolic constituents, e.g. cresols and dihydro-3,4-bis[(3-hydroxyphenyl)methyl]-2(3H)-furanone, known as HPMF, are contained in the solids content of the PMU. The natural mixture of estrogens contained in the PMU is largely present in conjugated form, e.g. as sulfuric acid semi-ester sodium salt (abbreviated hereafter as “sulfate salt”). The content of conjugated estrogens (abbreviated hereafter as “CE”), calculated as estrogen sulfate salt and relative to dry matter, may be between 0.3 and 1% by weight.
By separating out the undesirable accompanying substances, such as urea and in particular cresols and HPMF, usually extracts are obtained from the PMU which contain the conjugated estrogens from pregnant mares' urine (PMU) in dissolved form (solution extracts). More recent methods obtain natural mixtures of these conjugated estrogens (CE) by solid-phase extraction of the mixture of conjugated estrogens from pregnant mares' urine e.g. on RP silica gel (WO 98/08525) or on semipolar, in particular on non-ionic semipolar, polymeric adsorption resins (WO 98/08526). With these methods, the undesirable accompanying substances can be separated from the PMU effectively and efficiently and aqueous solution extracts of the CE of good quality can be obtained. The concentration of the CE in the solution extract is however subject to certain unavoidable fluctuations, since the PMU used for obtaining the CE as a natural starting material per se is subject to natural fluctuations in quality owing to its origin, storage, transport and any pre-processing etc.
In the production of pharmaceutical preparations of natural mixtures of conjugated equine estrogens from CE-containing solution extracts, a constant quality and metering strength of the preparation must be ensured. The natural fluctuations in the content of conjugated equine estrogens in the solution extracts used for the production of pharmaceutical preparations which occur as a function of the yield and quality of the starting material therefore have to be compensated for by suitable measures, in order to provide a material of constant quality and defined specification for further galenic processing.
There is therefore a need for suitable improved methods for conversion of the CE-containing aqueous solution extracts obtained by working up PMU into a solid galenic preformulation which is as protective of the product as possible, which contains the natural mixture of conjugated equine estrogens as active component in defined form and concentration and in a homogeneous distribution and then can be used as solid pharmaceutical raw material containing active substance (“dry extract”) in simple manner for further galenic processing into solid forms, such as for example for tabletting or direct tabletting. The natural mixture of conjugated equine estrogens must therefore be present in a form which assures the chemical stability of the hormones, i.e. the conjugated estrogens contained in the mixtures, and which permits the processing of these hormones into a solid galenic form, e.g. a tablet.